Interpreting Biological Similarity: Ongoing Challenges for Diverse Decision Makers

Similarity is an elusive and complicated concept facing comparisons of biological molecules, as even minute changes to a molecule\u27s structure can dramatically affect its function in the body. Yet the flood of biologic drugs on the market will increasingly force these similarity comparisons. These concerns are particularly relevant to two groups of drugs: families of biologic drugs that closely resemble each other in structure and function, here termed similar-impact biologics, and the biosimilars, which are intended to closely approximate generic forms of biologic drugs. In bringing biologic drugs to the market, manufacturers are likely to face dual obstacles: FDA approval and patent protection. These hurdles are somewhat in tension with each other. The more similar biosimilars are to their pioneer counterparts, the more easily they may advance to market via the Biologics Price Competition and Innovation Act\u27s ( BPCIA ) new accelerated approval pathway. While the FDA has provided some guidance about how much similarity is likely to suffice, the standard is not yet clearly defined. In contrast, the more similar two drugs are to one another, the less likely that they will be able to obtain patent protection. Further, biologic drugs pose special issues when considering various legal factors required for patentability. Resolving these questions for the optimal benefit of all stakeholders requires both fundamental institutional competency and a willingness on the part of decision makers to engage with difficult scientific questions. This Note explores these ongoing challenges, with particular focus on the clinical and litigation history of the TNFá inhibitors Humira, Enbrel, and Remicade

Interpreting Biological Similarity: Ongoing Challenges for Diverse Decision Makers

Similarity is an elusive and complicated concept facing comparisons of biological molecules, as even minute changes to a molecule\u27s structure can dramatically affect its function in the body. Yet the flood of biologic drugs on the market will increasingly force these similarity comparisons. These concerns are particularly relevant to two groups of drugs: families of biologic drugs that closely resemble each other in structure and function, here termed similar-impact biologics, and the biosimilars, which are intended to closely approximate generic forms of biologic drugs. In bringing biologic drugs to the market, manufacturers are likely to face dual obstacles: FDA approval and patent protection. These hurdles are somewhat in tension with each other. The more similar biosimilars are to their pioneer counterparts, the more easily they may advance to market via the Biologics Price Competition and Innovation Act\u27s ( BPCIA ) new accelerated approval pathway. While the FDA has provided some guidance about how much similarity is likely to suffice, the standard is not yet clearly defined. In contrast, the more similar two drugs are to one another, the less likely that they will be able to obtain patent protection. Further, biologic drugs pose special issues when considering various legal factors required for patentability. Resolving these questions for the optimal benefit of all stakeholders requires both fundamental institutional competency and a willingness on the part of decision makers to engage with difficult scientific questions. This Note explores these ongoing challenges, with particular focus on the clinical and litigation history of the TNFá inhibitors Humira, Enbrel, and Remicade

The Relationship Between Vitamin D Status and Body Mass Index in a Racially Diverse Urban Population of Male and Female Pre- and Early Adolescents

Objectives: To assess the association between serum 25(OH)D and body mass index (BMI) in pre- and early-adolescents and to determine whether this association varies by demographic/clinical characteristics. Methods: Vitamin D status was determined using serum 25(OH)D in healthy pre- and early adolescents in Pittsburgh, PA (deficiency=/mL, insufficiency=12-/mL, sufficiency=≥20 ng/mL). Adiposity was quantified using BMI percentile (normal=\u3c85th, overweight=\u3e85th-95th, obese=\u3e95th). The relationship between serum 25(OH)D and adiposity was assessed in the total population and after stratification by gender, race, Fitzpatrick skin type, age, and Tanner stage. Results: 294 children (mean age 10.2 + 2.1 years; 60% African American; median serum 25(OH)D=27.0 ng/mL) were studied. Serum 25(OH)D was significantly lower in obese (n=72) vs. overweight (n=48) and normal weight (n=171) participants at 23.6, 29.5, and 28.2 ng/mL, respectively; p=0.015. This trend remained significant for early adolescents but did not differ after stratification by other demographic/clinical characteristics. A significant negative correlation was found between BMI and serum 25(OH)D (r = -0.315; p=0.000). Regression analysis predicted that 25% of the variance in serum 25(OH)D levels was attributed to BMI, gender, race, skin type, age, pubertal status, daily vitamin D and calcium intake, sun exposure, and sunscreen use, with Tanner stage being the only significant independent predictor. Conclusions: A significant inverse association between serum 25(OH)D and adiposity was observed in a population of pre- and early adolescents. This relationship was stronger in early adolescents. A meta-analysis to further explore this association in pediatric populations is warranted

Simulated Atmospheric N Deposition Alters Fungal Community Composition and Suppresses Ligninolytic Gene Expression in a Northern Hardwood Forest

High levels of atmospheric nitrogen (N) deposition may result in greater terrestrial carbon (C) storage. In a northern hardwood ecosystem, exposure to over a decade of simulated N deposition increased C storage in soil by slowing litter decay rates, rather than increasing detrital inputs. To understand the mechanisms underlying this response, we focused on the saprotrophic fungal community residing in the forest floor and employed molecular genetic approaches to determine if the slower decomposition rates resulted from down-regulation of the transcription of key lignocellulolytic genes, by a change in fungal community composition, or by a combination of the two mechanisms. Our results indicate that across four Acer-dominated forest stands spanning a 500-km transect, community-scale expression of the cellulolytic gene cbhI under elevated N deposition did not differ significantly from that under ambient levels of N deposition. In contrast, expression of the ligninolytic gene lcc was significantly down-regulated by a factor of 2–4 fold relative to its expression under ambient N deposition. Fungal community composition was examined at the most southerly of the four sites, in which consistently lower levels of cbhI and lcc gene expression were observed over a two-year period. We recovered 19 basidiomycete and 28 ascomycete rDNA 28S operational taxonomic units; Athelia, Sistotrema, Ceratobasidium and Ceratosebacina taxa dominated the basidiomycete assemblage, and Leotiomycetes dominated the ascomycetes. Simulated N deposition increased the proportion of basidiomycete sequences recovered from forest floor, whereas the proportion of ascomycetes in the community was significantly lower under elevated N deposition. Our results suggest that chronic atmospheric N deposition may lower decomposition rates through a combination of reduced expression of ligninolytic genes such as lcc, and compositional changes in the fungal community

Mapping local patterns of childhood overweight and wasting in low- and middle-income countries between 2000 and 2017

A double burden of malnutrition occurs when individuals, household members or communities experience both undernutrition and overweight. Here, we show geospatial estimates of overweight and wasting prevalence among children under 5 years of age in 105 low- and middle-income countries (LMICs) from 2000 to 2017 and aggregate these to policy-relevant administrative units. Wasting decreased overall across LMICs between 2000 and 2017, from 8.4% (62.3 (55.1–70.8) million) to 6.4% (58.3 (47.6–70.7) million), but is predicted to remain above the World Health Organization’s Global Nutrition Target of <5% in over half of LMICs by 2025. Prevalence of overweight increased from 5.2% (30 (22.8–38.5) million) in 2000 to 6.0% (55.5 (44.8–67.9) million) children aged under 5 years in 2017. Areas most affected by double burden of malnutrition were located in Indonesia, Thailand, southeastern China, Botswana, Cameroon and central Nigeria. Our estimates provide a new perspective to researchers, policy makers and public health agencies in their efforts to address this global childhood syndemic

Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity

To gain further insight into the genetic architecture of psoriasis, we conducted a meta-analysis of 3 genome-wide association studies (GWAS) and 2 independent data sets genotyped on the Immunochip, including 10,588 cases and 22,806 controls. We identified 15 new susceptibility loci, increasing to 36 the number associated with psoriasis in European individuals. We also identified, using conditional analyses, five independent signals within previously known loci. The newly identified loci shared with other autoimmune diseases include candidate genes with roles in regulating T-cell function (such as RUNX3, TAGAP and STAT3). Notably, they included candidate genes whose products are involved in innate host defense, including interferon-mediated antiviral responses (DDX58), macrophage activation (ZC3H12C) and nuclear factor (NF)-κB signaling (CARD14 and CARM1). These results portend a better understanding of shared and distinctive genetic determinants of immune-mediated inflammatory disorders and emphasize the importance of the skin in innate and acquired host defense

Production, Characterisation and Testing of an Ovine Antitoxin against Ricin; Efficacy, Potency and Mechanisms of Action

Ricin is a type II ribosome-inactivating toxin that catalytically inactivates ribosomes ultimately leading to cell death. The toxicity of ricin along with the prevalence of castor beans (its natural source) has led to its increased notoriety and incidences of nefarious use. Despite these concerns, there are no licensed therapies available for treating ricin intoxication. Here, we describe the development of a F(ab’)2 polyclonal ovine antitoxin against ricin and demonstrate the efficacy of a single, post-exposure, administration in an in vivo murine model of intoxication against aerosolised ricin. We found that a single dose of antitoxin afforded a wide window of opportunity for effective treatment with 100% protection observed in mice challenged with aerosolised ricin when given 24 h after exposure to the toxin and 75% protection when given at 30 h. Treated mice had reduced weight loss and clinical signs of intoxication compared to the untreated control group. Finally, using imaging flow cytometry, it was found that both cellular uptake and intracellular trafficking of ricin toxin to the Golgi apparatus was reduced in the presence of the antitoxin suggesting both actions can contribute to the therapeutic mechanism of a polyclonal antitoxin. Collectively, the research highlights the significant potential of the ovine F(ab’)2 antitoxin as a treatment for ricin intoxication